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J. Biol. Chem., Vol. 282, Issue 31, 22267-22277, August 3, 2007

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Chaperone Functions of the E3 Ubiquitin Ligase CHIP^*

Meredith F. N. Rosser¹, Erin Washburn, Paul J. Muchowski², Cam Patterson^¶3, and Douglas M. Cyr^||4

From the Department of Cell and Developmental Biology, ^¶Carolina Cardiovascular Biology Center, and ^||University of North Carolina Cystic Fibrosis Center, University of North Carolina Chapel Hill School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599 and the Gladstone Institute of Neurological Disease, Department of Biochemistry and Biophysics and Department of Neurology, University of California, San Francisco, California 94158

The carboxyl terminus of the Hsc70-interacting protein (CHIP) is an Hsp70 co-chaperone as well as an E3 ubiquitin ligase that protects cells from proteotoxic stress. The abilities of CHIP to interact with Hsp70 and function as a ubiquitin ligase place CHIP at a pivotal position in the protein quality control system, where its entrance into Hsp70-substrate complexes partitions nonnative proteins toward degradation. However, the manner by which Hsp70 substrates are selected for ubiquitination by CHIP is not well understood. We discovered that CHIP possesses an intrinsic chaperone activity that enables it to selectively recognize and bind nonnative proteins. Interestingly, the chaperone function of CHIP is temperature-sensitive and is dramatically enhanced by heat stress. The ability of CHIP to recognize nonnative protein structure may aid in selection of slow folding or misfolded polypeptides for ubiquitination.

Received for publication, January 18, 2007 , and in revised form, May 31, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by SPIRE Postdoctoral Fellowship Grant GM 000678-08 through NIGMS, National Institutes of Health (NIH).

² Supported by NINDS, NIH Grants NS 047237 and NS 054753.

³ Supported by NIH Grant GM 061728.

⁴ Work in this author's laboratory is supported by NIH Grant GM 056981 and the Cystic Fibrosis Foundation. To whom correspondence should be addressed: Dept. of Cell and Developmental Biology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599. Tel.: 919-843-4805; E-mail: DMCYR{at}med.unc.edu.

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